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Current Issues in the US:Caring for the Patient beyond HIV Infection

Ann M. Khalsa, MD, MSEd, AAHIVSMcDowell (HIV/AIDS) Healthcare Center, MIHS

Arizona AIDS Education and Training CenterPhoenix, Arizona, USA

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Case Outline Anneliese H.

Diabetes Hyperlipidemia Antiretroviral selection

Teri A. Coronary heart disease Hepatitis C Antiretroviral selection

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Anneliese – Case Overview 42 year old heterosexual Caucasian female, Dx HIV+ 2002

SH: Divorced female, lost custody of 3 childrenRecurrent adult cocaine use (rehab programs twice)History of childhood abuse2007 lost job and insurance

FH: Diabetes, hypertension, bipolar disease, CAD (father MI at 60yr)

PMH: DiabetesHyperlipidemiaCervical dysplasiaDepression with mood swings

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Anneliese – Case Overview 3/2009: new to clinic – following 2 year off prescriptions

Sx: polyuria, polydipsia, 15lb wt loss, GERD, depression with mood swings, genital herpes

PE: BMI 27, Waist 91cm, BP 110/70

2002-2007 3/2009 CD4 # / % 500s 82 / 6%HIV-1 RNA UD on ARV 122,000ARV TDF-FTC-ATVr Off meds

Comments1.5 year total ARV,

Hx rash with EFV GT negative

Other ResultsCreat 0.81, Ur Prot neg

TC 141 / TGA 758 / HDL 26Gluc 253 / HgbA1c 9.6

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Anneliese – ?# 1 Which of the following therapies need to be

started urgently?

1) Antiretroviral therapy

2) OI prophylaxis

3) Diabetes therapy

4) Lipid lowering therapy

5) Anti-depressants

Check all that apply

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Anneliese – ?# 1 Answer Most urgent treatments?

1) Initiation of antiretroviral therapy

2) Initiation of OI prophylaxis

3) Initiation of diabetes therapy

4) Initiation of lipid lowering therapy

5) Initiation of anti-depressants

Potential immediate complications

Underlies ultimate treatment success

Confounded by high glucose, potential pancreatitis risk

May underlie ultimate treatment success

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Anneliese – Case Follow-Up She was started initially on the following:

SMX-TMP 800/160mg – once daily

Metformin 500mg – twice daily

Gemfibrozil 600mg – twice daily

Acyclovir 400 mg – twice daily

(all available through discount pharmacy program)

Antiretrovirals not initially available due to lack of funding

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Anneliese –?# 2 At her follow-up appointment 2 months later she was

tolerating the metformin and gemfibrozil, but her random glucose in clinic was 301. Which of the following would be your next step in treating her diabetes?

1) Intensive dietary modification

2) Increased metformin dose

3) Metformin combined with a sulfonylurea or a thiazolinedione

4) Short and long acting Insulin

--- Choose all that apply ---

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Anneliese –?# 2 Answer Which one of the following would be your

next step in treating her diabetes?

1) Intensive dietary modification Counseling done

2) Increased metformin dose Increased to 850mg

3) Metformin combined with Glyburide addeda sulfonylurea or a thiazolinedione

4) Short and long acting Insulin

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Anneliese – ?# 2 Discussion Diabetes treatment sequence:

Hgb A1c Strategy Medications

6-7 Monotherapy Metformin, TZD, or sulfonylurea, or newer drug

7-8 Combination therapy 2 of the above

8-10Intensified combination therapy

Increased dosesMulti-class

>10 Insulin Long and short-acting

Am.Assoc.Clin.Endocrin. , Endocrine Practice 2007, 13:3-68;Am.Diab.Assoc., Diabetes Care 2010, 34:S11-S61.

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Anneliese – ?# 2 Discussion

Medication Advantages Disadvantages / Risks

Metformin Insulin resistanceNo weight gain NASH, TGA, LDL

Risk lactic acidosisCaution with renal or hepatic impairment or unstable CHF

Thiazolidinedione Insulin resistance TGA, HDL Endothelial function

Weight gainEdema (not in CHF)Caution in hepatic impairment

Sulfonylurea Insulin secretion Weight gain

Hypoglycemia

InsulinEffective after -cell failure Weight gain

Standard diabetes medications:

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Anneliese – ?# 2 Discussion Dietary recommendations:

Food Group Diabetes Hyperlipidemia

Fats: - Total- Saturated- Cholesterol

< 30%< 10% < 300 mg/d

25-35%< 7% (if high LDL)< 200 md/d

Soluble Fiber 25-50 g/d 10-25 g/d

Carbohydrates “Low carbohydrate”whole grains, fruits/vegies

50-60%whole grains, fruits/vegies

Other Insulin resistance: - 500-1000 calories - 5-7% weight loss

plant sterols and stanols

(% of total daily calories)

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Anneliese – ?# 3 In July 2009 the patient was able to start ARVs. She reports an

irregular eating schedule and problems with adherence. Which of the following 3rd ARV agents would be appropriate along with a 2-NRTI backbone?

1) Atazanavir-ritonavir

2) Darunavir-ritonavir

3) Efavirenz

4) Fosamprenavir-ritonavir

5) Lopinavir-ritonavir

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Anneliese – ?# 3 3rd ARV agents options:

1) Atazanavir-ritonavir

2) Darunavir-ritonavir

3) Efavirenz

4) Fosamprenavir-ritonavir

5) Lopinavir-ritonavir

Antacid caution

Dosing with food

History of rash and mood disorder

Dosing without food

Higher rate TGA

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Anneliese – Case Follow-Up

3/2009 5/2009 7/2009 8/2009 1/2010

CD4 # 82 / 6% -- 71/10% 116/12%

HIV-1 RNA 122,000 -- 212 <75

ARV Off meds None ABC-3TC-FPVr - Same - Same

TC/TGA/HDL 141/ 758 /26 -- -- 254 / 879 / 31

FBS/HgbA1c 253 / 9.6 318 / 8.1 269 / 7.7

MedicationsStart Dates

- Metformin 500 bid

- Gemfibrozil 600 bid

- Metformin 850 bid- Glyburide 10mg daily- Same

- Same

- Same

- Same

- Same

- Same

- Same

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Anneliese – ?# 4 The patient has achieved viral suppression with beginning

immune recovery. What additional steps can be taken to control her glucose and lipids?

1) Evaluate for secondary causes of dyslipidemia

2) Add additional lipid reducing medications

3) Add additional glucose reducing medications

4) Reinforce lifestyle changes of diet and exercise

5) Change antiretroviral regimen

--- check all that apply ---

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Anneliese – ?# 4 Answer The patient has achieved viral suppression with beginning

immune recovery. What additional steps can be taken to control her glucose and lipids?

1) Evaluate for secondary causes of dyslipidemia

2) Add additional lipid reducing medications

3) Add additional glucose reducing medications

4) Reinforce lifestyle changes of diet and exercise

5) Change antiretroviral regimen --- also an option

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Anneliese – ?#4 Discussion Secondary causes of hypertriglyceridemia:

Diseases: hyperglycemia , chronic kidney disease, HIV Lifestyle: alcohol, smoking, inactivity, high carbohydrate

diet, overweight Drugs: estrogens, thiazides, -blockers, steroids, protease

inhibitors Additional treatments for hypertriglyceridemia:

Niacin: problematic side effect of hyperglycemia Omega 3: additional cardio-protective benefit Statins: anti-inflammatory and cardio-protective benefit

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Anneliese – Case Follow-Up

3/2009 7/2009 1/2010 12/2010

CD4 # 82 / 6% 116/12% 24/5%

HIV-1 RNA 122,000 <75 26,053

ARV Off meds ABC-3TC-FPVr Same Off meds

TC/ TGA/HDL/ LDL

141/ 758 / 26/ --

254 / 879 / 31/ --

278/ 1904/27/ --

FBS/HgbA1c 253 / 9.6 269 / 7.7 334 / 11.8

Meds-Met.5002 -Gem.6002

-Met.8502

-Glyb. 101

-Gem.6002

SameSameSame

Off meds

The patient returns after 10 month absence from clinic due to loss of insurance. She's treated for candida vaginitis.

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Anneliese – ?# 5 In addition to providing OI prophylaxis and restarting

gemfibrozil, how would you manage her ARVs and DM medications at this time?

1) Resume prior ARVs and oral diabetes regimen

2) Resume prior meds and add insulin

3) Start new ARV regimen while resuming her prior oral diabetes regimen

4) Start new ARV regimen, resume her prior oral diabetes regimen and add insulin

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Anneliese – ?# 5 Answer In addition to providing OI prophylaxis and restarting

gemfibrozil, how would you manage her ARVs and DM medications at this time?

1) Resume prior ARVs and oral diabetes regimen

2) Resume prior meds and add insulin

3) Start new ARV regimen while resuming her prior oral diabetes regimen

4) Start new ARV regimen, resume her prior oral diabetes regimen and add insulin

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Anneliese H – Case Follow-Up

3/2009 7/2009 1/2010 12/2010 3/2011

CD4 # 82 / 6% 116/12% 24/5% 37/7%

HIV-1 RNA 122,000 <75 26,053 423

ARV Off meds ABC-3TC-FPVr Same Off meds ABC-3TC-

FPVr

TC/ TGA/HDL/ LDL

141/ 758 / 26/ --

254 / 879 / 31/

--

278/ 1904/27 / --

265/ 486/31/ 132

FBS/HgbA1c 253 / 9.6 269 / 7.7 334 / 11.8 302 / 10.6

Meds-Met.5002 -Gem.6002

-Met.8502

-Glyb. 101

-Gem.6002

SameSameSame

Off meds-Met.8502

-Glyb. 101

-Gem.6002

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Anneliese – ?# 6 Her HIV and lipid status show good initial improvement

but her diabetes remains poorly controlled. What additional step/s would you take to control her diabetes?

1) Increase dose of metformin

2) Add thiazolidinedione

3) Add “post-prandial” newer agent

4) Change to combined short and long-acting insulin regimen

5) Add thiazolidinedione and long-acting insulin

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Anneliese – ?# 6 Answer Additional step/s to control her diabetes?

1) Increase dose of metformin Insufficient

2) Add thiazolidinedione Option

3) Add “post-prandial” Need home glucosenewer agent testing

4) Change to combined short Difficult adherenceand long-acting insulin regimen

5) Long-acting insulin Insulin recommended

@ HgbA1c >10

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Anneliese – ?#6 Discussion

INSULINS Onset Peak Dur’nAspart (NovoLog) Lispro (Humalog)Glulisine (Apidra)

5-15m 30-90m <5h

Regular 30-60m 2-3h 5-8hNPH 2-4h 4-10h 10-16hGlargine (Lantus) 2-4h No peak 20-24hDetemir (Levemir) 3-8h No peak 6-23h

Current insulin recommendations (HgbA1c >10): Long-acting basal (Lantus, Levemir or NPH) ---plus--- Rapid acting synthetics (Aspart, Lispro, Glulisoline)

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Anneliese – ?#6 Discussion Newer diabetes medications:

Post-prandial glucose ( microvascular complications): Glinides + erratic eating schedules

- Renal or hepatic impairment, $$ -Glucosidase - GI side effects; glucose tablets for rescue

inhibitors - Renal or hepatic impairment Sitagliptan + weight loss

- diarrhea, $$

Gastric empyting (satiety): Exentatide + no weight gain, minimal

hypoglycemia Pramlinitide + weight loss, - injectable with insulin, $$

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Anneliese H – Case Follow-Up

3/2009 7/2009 1/2010 12/2010 3/2011 6/2011

CD4 # 82 / 6% 116/12% 24/5% 37/7% 58/8%

HIV-1 RNA 122,000 <75 26,053 423 <40

ARV Off meds ABC-3TC-FPVr Same Off meds ABC-3TC-

FPVr Same

TC/ TGA/HDL/ LDL

141/ 758 / 26/ --

254 / 879 / 31/ --

278/1904/27

265/ 486/31/ 132

312/ 502/35/ 166

FBS/HgbA1c 253 / 9.6 269 / 7.7 334 / 11.8 302 / 10.6 87 / 7.1

Meds-Met.5002 -Gem.6002

-Met.8502

-Glyb. 101

-Gem.6002

SameSameSame

Off meds

-Met.8502

-Glyb. 101

-Gem.6002

-Lantus HS

SameSameSameSame

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Case Outline Anneliese H.

Diabetes Hyperlipidemia Antiretroviral selection

Teri A. Coronary heart disease Hepatitis C Antiretroviral selection

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Teri A – Case Overview 53 year old Caucasian heterosexual female Hospitalized for MI and Diagnosed HIV+ and HCV+

8/2010 Tested due to thrombocytopenia and transaminitis

in context of risk history HIV- in 2000, never tested for HCV HCV source: ex-partner (2002-2009) HIV source unknown

Risk factors: past hx of drugs and prostitution

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Teri A – Case Overview No medical care prior to moving to AZ in 4/2010 PMH: Post-menopausal since 2002

Shingles in 1/2010STDs and PID, G6 P1 (CSxn) SAb 2 TAb 3

SH: Cocaine and methamphetamine 1984-2002Prostitution 1995-2003Smoking: 30 pack-yearsChildhood sexual abuse by father

FH: Mother with colon cancer Paternal grandfather died of MI in 60s

Father alcoholic

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Teri A – CAD Overview 8/2010 hospitalized for acute MI:

Left sided chest heaviness, at rest while smoking first cigarette of the morning, accompanied by diaphoresis and SOB

EKG: bradycardia (HR=50) with T-wave inversions and ST depression in anterolateral chest leads

Successive Troponin-I elevation:

Time (hr): 1 hr 5 hrs 8 hrs 18 hs 21 hrs

(NL <0.06) 0.05 1.05 1.81 4.68 5.06

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Teri A – CAD Overview Only prior symptom was SOBOE with bicycle riding Sx resolved in ED with nitropaste, aspirin, integrilin

(platelet inhibitor), lovenox, and metoprolol Cath lab:

LAD 40% occlusive lesion midvessel RCA 50% occlusive proximal lesion, plus

near complete occlusion distal vessel Tx: Extraction thrombectomy with percutaneous

transluminal coronary angioplasty distal RCA

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Teri A – CAD Overview Echocardiogram:

No regional wall abnormalities Severe left atrial enlargement with

moderately-severe diastolic dysfunction Mild pulmonary hypertension Preserved LV systolic function Normal valves with mild mitral regurgitation

Patient was discharged from the hospital

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Teri – CAD ?#1 In the HIV clinic, management of her coronary artery

disease should include treatment with all the following EXCEPT?1) Alpha-blockers 2) Beta-blockers3) ACE inhibitors4) Aspirin5) Statins6) Omega 3

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Teri – CAD ?#1 Answer Management of her coronary artery disease

should include treatment with all the following EXCEPT?1) Alpha-blockers: no CAD benefit2) Beta-blockers: improved CVD outcome post

MI3) ACE inhibitors: Nitric Oxide,

improved CVD outcome post MI

4) Aspirin: inhibits platelet aggregation5) Statins: Nitric Oxide, LDL6) Omega 3: endothelial function, HDL

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Teri – CAD ?#1 Discussion General CAD management:

Beta-blockers goal HR 50-60 ACE inhibitors expect 20-30% creatinine

via intraglomerular pressure Aspirin 81-325 mg daily Statins 1 goal LDL <70-100 Omega 3 2 goal HDL >40 Exercise Nitric Oxide Smoking cessation vasospasm, atherogenesis, etc Depression 15-20% post MI incidence

independent predictor mortallity

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Teri – CAD Case Discussion CAD follow-up:

Treated with: Metoprolol 25 mg twice daily Aspirin 81 mg daily Lisinopril 2.5 mg daily Omega 3 capsules 1000 mg twice daily

Repeatedly encouraged to stop smoking Encouraged to exercise

Limited by SOBOE and fatigue (HCV and anemia) Atorvastatin was deferred during HCV treatment

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Teri – ARV ?#2 In the context of CAD and HCV infection which of one

of the following antiretroviral medications does NOT have possible reasons to AVOID its usage?

1) Abacavir2) Efavirenz 3) Lopinavir4) Raltegravir5) Ritonavir6) Tenofovir

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Teri – ARV ?#2 Answer In the context of CAD and HCV infection which of one

of the following antiretroviral medications does NOT have possible reasons to AVOID its usage?

1) Abacavir cohort “signal” of MI association2) Efavirenz risk of hyperlipidemia3) Lopinavir cohort “signal” of MI association4) Raltegravir5) Ritonavir risk of hyperlipidemia6) Tenofovir risk of nephrotoxicity (HCV & renal

atrophy)

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Teri – Antiretroviral Treatment

9/23/2010 11/4/2010 3/10/2011WBC 3500 4300 5200Lymphocyte 1200 1900 2400CD4 Cell abs 257 345 426CD4 % Helper T Cell 21 22 23CD4/CD8 Ratio 0.3 0.3 0.4HIV-1 RNA Quant 11813 (H) <75 NOT DET

Baseline: GT neg, HLA B*5701 neg ARV: 3TC-ETV-RAL started 10/2010

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Teri – HCV ?#3 In the context of her CAD infection how would you

manage her hepatitis C infection?1) Avoid peg-interferon and ribavirin for one year

following the MI due to risk of anemia2) Evaluate and treat the HCV whenever the patient is

stable and ready3) Avoid peg-interferon and ribavirin entirely due to

medication toxicity4) Consider HCV treatment only if starts to develop

significant liver fibrosis

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Teri – HCV ?#3 Answer In the context of her CAD infection how would you

manage her hepatitis C infection?

1) Avoid for one year due to anemia:diligently manage, but not contraindication

2) Evaluate and treat the HCV whenever the patient is stable and ready

3) Avoid entirely: no cardio-toxicity4) Only if significant liver fibrosis: not required to wait

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Teri – HCV ?#4 Which of the following factors are NOT prognostic of

her response to HCV treatment?

1) Fasting glucose

2) HCV genotype

3) HCV quantitative RNA

4) Routine liver ultrasound

5) Liver biopsy

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Teri – HCV ?#4 Answer

Which of the following parameters will NOT affect her response to HCV treatment?

1) Fasting glucose

2) HCV genotype

3) HCV quant. RNA

4) Routine Liver ultrasound

5) Liver biopsy

Associated with Poorer Response:

Insulin resistance

GT 1

High

Not applicable

Bridging fibrosis

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Teri A – HCV Staging Results Abdominal ultrasound 12/2010:

Hepatosplenomegaly with 1.5 cm liver lesion Left renal atrophy (7.7cm length vs 12.4 cm / right) No ascites

Abdominal CT 1/2011: Hepatic nodularity, isolated hemangioma Left renal cortical scarring

Liver needle core biopsy 3/2011: Moderate portal, periportal and lobular inflammation Stage 2-3 portal fibrosis with occasional bridging fibrosis

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Teri – HCV ?#4 DiscussionPrognostic factors Positive Predictors of Success

Age 53 years No BMI 23 Yes Genotype 3a Yes HCV RNA 2,186,720 No Fibrosis Partial bridging No/Yes Glucose 93 Yes CD4 After ARV = 426 Yes HIV RNA After ARV = <40 Yes Drugs/EtOH No Yes Psych No Yes

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Teri – ARV Treatment Follow-Up

9/23/2010 11/4/2010 3/10/2011 6/6/2011 8/31/2011CD4 T Cell Abs 257 345 426 348 250CD4 % Helper T Cell 21 22 23 31 46CD4/CD8 Ratio 0.3 0.3 0.4 0.6 1.1HIV-1 RNA Quant 11813 (H) <75 NOT DET NOT DET NOT DETHep C RNA Quantitative, bDNA

-- 2,186,720 -- 18,992 <5

HIV treatment: 3TC-ETV-RAL since 10/2010 HCV treatment: RBV-PegIFN2a since

5/2/2011

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Disease Assessment Follow-Up Frequency

Comments

CVD • Risk assessment Framingham score

• EKG Conditional Consider prior to PI with potential conduction problems

HTN • Blood pressure Annual

Lipids • TC, HDL, LDL, TG Annual Repeat fasting prior to medical intervention

Diabetes • Fasting plasma glucose 6-12 m

• HgbA1c or oral GTT Conditional if fasting glucose > 100-125 mg/dl (5.7-6.9 mmol/L)

Renal • Risk assessment Annual CKD, DM, HTN, CVD, HCV, medications, family history

• eGFR 3-12 m More often if: CKD or risk factors present; or if on nephrotoxic drugs

(ARV: TDF, IDV, ATV; OI: ganciclovir, amphoterocin; etc.)• Urine dipstick: protein,

blood6-12 m Every 6 mo if eGFR <60 ml/min

• Spot urine Prot:Creat Conditional If proteinuria 1+ or eGFR <60 ml/min

Bone • Calcium, PO4, AlkPhos 6-12 m

• Risk assessment 2 y FRAX score in patients >40 yr

• DXA scan Conditional In at-risk patients

• 25OH Vit D Conditional In at-risk patients: malabsorption, PO4 wasting, dark skin, CKD, dietary deficiency, lack of sunlight exposure

Screening for Non-Infectious Co-MorbiditiesAdapted from EACS Guidelines October 2011

http://www.europeanaidsclinicalsociety.org/

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Disease Assessment Follow-Up Frequency

Comments

Liver •Risk assessment Annual More frequent on hepatotoxic drugs

•ALT/AST, AlkPhos, Bilirubin 3-12 m

NeuroCog •Screening questions 2 yrs Rule out confounding conditions

Depression •Screening questions 1-2 yrs More frequent in at-risk patients

Cancer •Mammography 1-3 yrs W: 50-70 yrs or W/M: high risk history

•Cervical Pap•Colposcopy

1-3 yrs W: Sexually activeFor ASCUS Pap

•DRE and Anal Pap

•Anoscopy

1-3 yrs MSM: evidence preliminaryM/W: high risk (HPV dis or RAI)For ASCUS Pap

•Ultrasound and AFP 6 mo Patients with cirrhosis – from any cause

•DRE PSA 1-3 yrs M >50, or high risk

•FOBT or •Colonoscopy

1-3 yrs 5-10 yrs

50-75 yrs, or high risk

Screening for Non-Infectious Co-Morbidities- Continued

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